Inflammatory disorders are characterized by their systemic effects. Inflammation is the body's response to injury, infection or molecules perceived by the immune system as foreign. Clinically, inflammation is characterized by pain, redness, heat, swelling and altered function of affected tissue. Although the ability to mount an inflammatory response is essential for survival, the ability to control inflammation is also necessary for health.
Examples of chronic systemic inflammation disorders include inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and multiple sclerosis (MS).
Inflammatory bowel disease (IBD) is a chronic autoimmune disease affecting the gastrointestinal tract with symptoms of abdominal pain, vomiting, diarrhea, hematochezia, and weight loss. IBD comes in two main forms, ulcerative colitis (UC) and Cohn's disease (CD). UC exclusively affects the colon and rectum, whereas CD may affect the entire gastrointestinal tract. Histologically UC is characterized by extended mucosal inflammation in contrast to CD, where deep punctuate lesions affects all layers of the intestinal wall. Initial stage IBD is currently treated medically by steroids, such as budesonide or aminosalicylates such as sulfasalazine, or by general immunosuppressants, such as azathioprine, whereas later stage severe cases require surgery, often in form of colostomy. Recently, antibodies against TNF-α have also been used clinically with some success.
Rheumatoid arthritis (RA) causes chronic inflammation of the joints and inflammation of the tissue around the joints, as well as other organs in the body. While rheumatoid arthritis is a chronic illness, patients may experience long periods without symptoms. Typically, however, rheumatoid arthritis is a progressive illness that has the potential to cause joint destruction and functional disability.
Multiple sclerosis (MS) is a debilitating chronic inflammatory disease that affects the central nervous system. Current research suggests that the illness is initiated by an autoimmune malfunction, where the body incorrectly directs certain leukocytes against proteins in the protective myelin sheath surrounding nerves in the brain and spinal cord. The result is multiple areas of scarring or sclerosis. Eventually, progressive damage can obliterate the nerve signals that control muscle coordination, strength, sensation and even vision.
WO 00/50026 describes Gardos channel antagonists (i.e. Ca2+-activated K-channels), which inhibit the Gardos channel of erythrocytes, reduce sickle erythrocyte dehydration and/or delay the occurrence of erythrocyte sickling or deformation. However, the effect of such compounds with respect to inflammatory conditions is not reported.
WO 01/27070 describes the use of carbonylamino derivatives for treating CNS disorders relating to metabotropic glutamate receptor antagonists and/or agonists. However, the effect of such compounds with respect to inflammatory conditions is not reported.
WO 03/004010 describes a particular group of carbonylamino derivatives for the treatment or alleviation of diseases or conditions relating to immune regulation. However, the effect of such compounds with respect to inflammatory conditions is not reported.
WO 03/059873 describes certain carbonylamino derivatives useful as potassium channel modulators. However, the effect of such compounds with respect to inflammatory conditions is not reported.